Aβ mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease (original) (raw)

Aβ mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease

2017, The Journal of neuroscience : the official journal of the Society for Neuroscience

Dendritic spine loss is recognized as an early feature of Alzheimer's disease, however the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased G-actin, as early as 1 month of age in a mouse model of Alzheimer's disease (AD; APPswe/PS1ΔE9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1ΔE9 male mice, which could be reversed by actin polymerizing agent, jasplakinolide. Further, F-actin depolymerizing agent, latrunculin, induced recall deficit following cFC in WT mice indicating the importance of maintaining F/G-actin equilibrium for optimal behavioral response. Using dSTORM, we show that F-actin depolymerization in spines leads to breakdown of nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1ΔE9 mice. Our results demonstrate that syn...